What is the recommended initial treatment for rheumatoid arthritis?

Treatment of Rheumatoid Arthritis

First-Line Therapy: Methotrexate with Glucocorticoid Bridge

Start methotrexate 15–25 mg orally once weekly with folic acid 1 mg daily immediately upon diagnosis, rapidly escalating to 25–30 mg weekly within 4–6 weeks, combined with low-dose prednisone ≤10 mg daily for up to 3 months as bridging therapy. 1, 2

• Methotrexate is the anchor disease-modifying antirheumatic drug (DMARD) because it demonstrates superior clinical and radiographic efficacy, slows joint damage progression, and has an acceptable safety profile when properly monitored. 1
• Delaying DMARD initiation beyond 3 months of symptom onset leads to irreversible joint damage and worse long-term functional outcomes. 1, 3
• If oral methotrexate at 20–25 mg weekly is poorly tolerated or ineffective after 3 months, switch to subcutaneous administration before declaring treatment failure. 1, 4
• Mandatory folic acid supplementation (1 mg daily) reduces methotrexate adverse effects and improves tolerability. 5, 1

Glucocorticoid Bridge Strategy

• Low-dose prednisone (≤10 mg/day or equivalent) provides rapid symptom control during the 6–12 week period before methotrexate becomes effective. 1
• Limit glucocorticoid exposure to less than 3 months and taper as quickly as clinically feasible; prolonged use beyond 1–2 years causes cumulative toxicity including osteoporosis, fractures, cataracts, and cardiovascular disease that outweighs any benefit. 5, 1, 4

Alternative First-Line Agents

• When methotrexate is contraindicated (severe renal impairment, active liver disease, pregnancy) or not tolerated early, use leflunomide or sulfasalazine as first-line alternatives. 1, 2
• Hydroxychloroquine monotherapy is inadequate for moderate-to-high disease activity because it has weak disease-modifying effects and no proven structural benefit. 4

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Treatment Targets and Monitoring Schedule

The primary goal is ACR/EULAR remission (SDAI ≤3.3, CDAI ≤2.8, or Boolean criteria: ≤1 tender joint, ≤1 swollen joint, CRP ≤1 mg/dL, patient global ≤1/10); if unattainable, low disease activity (SDAI ≤11 or CDAI ≤10) is acceptable. 1, 4

• Assess disease activity every 1–3 months during active disease using composite measures: tender/swollen joint counts (28-joint assessment), patient and physician global assessments, and inflammatory markers (ESR or CRP). 1
• Expect at least 50% improvement in disease activity within the first 3 months of therapy; failure to achieve this threshold mandates immediate treatment escalation. 5, 1
• The treatment target must be reached within 6 months; if not, therapy must be escalated or modified. 1, 2
• DAS28 <2.6 is insufficiently stringent to define remission; use ACR/EULAR remission criteria instead. 1

Baseline Safety Screening

• Before initiating methotrexate, obtain complete blood count with differential, hepatic enzymes, renal function tests, and chest radiograph. 6
• Screen for tuberculosis (TST or IGRA) before starting any biologic DMARD or JAK inhibitor. 1
• Administer age-appropriate vaccines, including recombinant herpes zoster vaccine, at least 2–4 weeks before biologic therapy; live vaccines are contraindicated after B-cell depletion. 1

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Treatment Escalation Algorithm

At 3 Months: <50% Improvement

Patients WITHOUT poor prognostic factors:

• Add triple-DMARD therapy: methotrexate + sulfasalazine (starting 500 mg twice daily, escalating to 1000 mg twice daily) + hydroxychloroquine 400 mg daily. 1, 4

Patients WITH poor prognostic factors:

• Poor prognostic factors include: high rheumatoid factor or anti-CCP titers, DAS28 >5.1, early erosive changes on radiographs, or failure of two conventional synthetic DMARDs. 1
• Add a biologic DMARD or JAK inhibitor to methotrexate immediately. 1, 2

At 6 Months: Target Not Achieved

Add a biologic DMARD or JAK inhibitor to methotrexate if not already combined. 1, 2

First-Line Biologic Options

• TNF-α inhibitors (adalimumab, etanercept, infliximab, certolizumab pegol, golimumab) are preferred first-line biologic agents and should be combined with methotrexate for superior efficacy. 1, 2
• Alternative biologic classes include IL-6 receptor antagonists (tocilizumab, sarilumab), T-cell costimulation modulators (abatacept), or rituximab (particularly for seropositive patients or those with prior lymphoma). 1, 4
• JAK inhibitors (tofacitinib, baricitinib, upadacitinib) are appropriate when biologics are unsuitable or after biologic failure. 1, 2
• Biologic agents combined with methotrexate demonstrate superior efficacy compared with biologic monotherapy by reducing immunogenicity. 1, 2

After First Biologic Failure

• Switch to a biologic with a different mechanism of action rather than a second agent from the same class; registry and observational data show superior outcomes with a mechanism-switch. 1
• Allow 3–6 months to fully assess the efficacy of any newly introduced biologic or targeted synthetic DMARD before making further therapeutic changes. 5, 1

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Special Populations and Considerations

Elderly Patients (≥80 years)

• Initiate methotrexate at lower doses (10–15 mg weekly) in patients with reduced renal function (eGFR <70 mL/min) and titrate gradually toward 20 mg weekly as tolerated. 5, 1
• For elderly patients requiring biologic therapy, abatacept is preferred over TNF inhibitors because it provides comparable efficacy with lower infection risk. 1

Patients with Erosive Disease and High RF

• Combination therapy (methotrexate + hydroxychloroquine + sulfasalazine) is more effective than methotrexate monotherapy in patients with poor prognostic factors such as high rheumatoid factor levels and erosive disease. 4
• High-dose corticosteroids alone do not prevent radiographic progression and are not disease-modifying therapy. 4

Patients with Coexistent Inflammatory Bowel Disease

• Methotrexate provides no therapeutic effect on luminal ulcerative colitis; TNF inhibitors (infliximab, adalimumab, golimumab) are first-line agents for simultaneous control of joint and gut disease. 1
• Vedolizumab should be excluded because its gut-specific mechanism does not improve musculoskeletal manifestations and may paradoxically worsen arthritis. 1

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Critical Pitfalls to Avoid

• Do not delay DMARD initiation while awaiting specific serologic thresholds; treatment should start at diagnosis regardless of rheumatoid factor, anti-CCP, ESR, or CRP levels. 1
• Do not rely on NSAIDs or corticosteroids as sole therapy; they provide only symptomatic relief without disease modification and do not prevent radiographic joint damage. 1, 4
• Do not underdose methotrexate; ensure escalation to 20–25 mg weekly (oral or subcutaneous) before declaring treatment failure. 5, 1
• Do not continue ineffective therapy beyond 3–6 months without escalation; ongoing joint damage accumulates and becomes irreversible. 1, 3
• Do not use DAS28 <2.6 as the remission target; adopt ACR/EULAR remission criteria instead. 1
• Do not continue systemic corticosteroids beyond 1–2 years; cumulative adverse effects (fractures, cataracts, cardiovascular disease, osteoporosis) outweigh symptomatic benefits. 5, 1

Drug Interactions Requiring Caution

• NSAIDs and salicylates reduce tubular secretion of methotrexate and may enhance toxicity; use caution when administered concomitantly with methotrexate, particularly at higher doses. 6
• Penicillins may reduce renal clearance of methotrexate, leading to increased serum concentrations and hematologic/gastrointestinal toxicity; monitor carefully. 6
• Probenecid diminishes renal tubular transport of methotrexate; use with this drug should be carefully monitored. 6